Treatment of HIV-infected individuals is one of the most pressing biomedical problems of recent times. A promising new therapy has emerged as an important method for preventing or inhibiting the rapid proliferation of the virus in human tissue. HIV-protease inhibitors block a key enzymatic pathway in the virus resulting in substantially decreased viral loads, which slows the steady decay of the immune system and its resulting deleterious effects on human health. The HIV-protease inhibitor nelfinavir mesylate 
has been shown to be an effective treatment for HIV-infected individuals. Nelfinavir mesylate is disclosed in U.S. Pat. No. 5,484,926, issued Jan. 16, 1996. This patent is entirely incorporated by reference into this patent application. Methods for preparing nelfinavir mesylate from nelfinavir free base are disclosed in U.S. Pat. No. 5,484,926, as well as U.S. patent appln. Ser. No. 08/708,411 of inventors M. Deason and K. Whitten, entitled xe2x80x9cIntermediates for Making HIV-Protease Inhibitors and Methods of Making HIV-Protease Inhibitorsxe2x80x9d, filed on Sep. 5, 1996, which application is entirely incorporated herein by reference.
The present invention relates to the novel compounds illustrated below. These compounds are useful as intermediates and starting materials for the preparation of nelfinavir free base and nelfinavir mesylate.
A first compound according to this invention is a compound of formula 6, as follows: 
wherein each R3 is independently an aryl group or an alkyl group; or a pharmaceutically acceptable salt or solvate thereof.
A second compound according to this invention is a compound of formula 6a: 
wherein each X is independently a halogen; or a pharmaceutically acceptable salt or solvate thereof.
A third compound according to this invention is a compound of formula 7: 
wherein each R3 is independently an aryl group or an alkyl group; or a pharmaceutically acceptable salt or solvate thereof.
A fourth compound according to this invention is a compound of formula 8: 
wherein each R3 is independently an aryl group or an alkyl group; or a pharmaceutically acceptable salt or solvate thereof.
A fifth compound according to the invention is a compound of formula 9: 
wherein each R3 is independently an aryl group or an alkyl group; or a pharmaceutically acceptable salt or solvate thereof.
A sixth compound according to this invention is a compound of formula 10: 
wherein R3 is an aryl group or an alkyl group; or a pharmaceutically acceptable salt or solvate thereof.
A seventh compound according to this invention is a compound of formula 7a: 
wherein each R3 is independently an aryl group or an alkyl group; or a pharmaceutically acceptable salt or solvate thereof.
An eighth compound according to this invention is a compound of formula 8a: 
wherein R4 is an alkyl group; or a pharmaceutically acceptable salt or solvate thereof.
A ninth compound according to this invention is a compound of formula 9a: 
wherein R4 is an alkyl group; or a pharmaceutically acceptable salt or solvate thereof.
A tenth compound according to this invention is a compound of formula 10a: 
or a pharmaceutically acceptable salt or solvate thereof.
This invention further relates to processes for making and using the compounds and intermediates described above. For example, these compounds can be used to prepare nelfinavir free base and nelfinavir mesylate.
A first method according to the invention relates to a method of making a compound of formula 6: 
wherein each R3 is independently an aryl group or an alkyl group, by converting, under sufficient conditions, a compound of formula 5: 
wherein each R3 independently an aryl group or an alkyl group, to the compound of formula 6 shown above.
In a second method according to this invention, a compound of formula 6a is produced: 
wherein each X is independently a halogen. In this method, the compound according to formula 5 (illustrated above) is converted, under sufficient conditions, to the compound of formula 6a.
This invention further relates to methods of making a compound of formula 7: 
wherein each R3 is independently an aryl group or an alkyl group. In one method, a compound of formula 6: 
wherein each R3 is independently an aryl group or an alkyl group, is converted, under sufficient conditions, to the compound of formula 7. In another method, a compound according to formula 6a: 
wherein each X is independently a halogen, is converted, under sufficient conditions, to the compound of formula 7.
Another method according to this invention relates to a method of making a compound of formula 8: 
wherein each R3 is independently an aryl group or an alkyl group. The compound according to formula 8 is produced by converting, under sufficient conditions, a compound of formula 7: 
wherein each R3 is independently an aryl group or an alkyl group, to the compound of formula 8.
In another method according to this invention, a compound according to formula 8 (illustrated above), can be converted, under sufficient conditions, to a compound of formula 9: 
wherein each R3 is independently an aryl group or an alkyl group.
Yet another method according to this invention relates to a method of making a compound of formula 10: 
wherein R3 is an aryl group or an alkyl group. In this method, a compound of formula 9: 
wherein each R3 is independently an aryl group or an alkyl group, is converted, under sufficient conditions, to a compound of formula 10.
This invention also relates to a method of making a compound of formula 11: 
by converting, under sufficient conditions, a compound of formula 10: 
wherein R3 is an aryl group or an alkyl group, to a compound of formula 11.
As mentioned above, another compound or intermediate according to this invention is a compound of formula 7a: 
wherein each R3 is independently an aryl group or an alkyl group. This material can be made, in accordance with another method of this invention, by converting, under sufficient conditions, a compound of formula 6: 
wherein each R3 is independently an aryl group or an alkyl group, to the compound of formula 7a. In an alternative method according to this invention, the compound according to formula 7a (shown above) can be produced by converting, under sufficient conditions, a compound of formula 6a: 
wherein each X is independently a halogen, to the compound of formula 7a.
Another method according to this invention relates to a method of making a compound of formula 8a: 
wherein R4 is an alkyl group. This compound is produced by converting, under sufficient conditions, a compound of formula 7a: 
wherein each R3 is independently an aryl group or an alkyl group, to the compound of formula 8a.
In another method according to the invention, a compound of formula 9a: 
wherein R4 is an alkyl group, can be produced by converting, under sufficient conditions, a compound of formula 8a: 
wherein R4 is an alkyl group, to the compound of formula 9a.
Yet another method according to this invention relates to a method of making a compound of formula 10a: 
by converting, under sufficient conditions, a compound of formula 9a: 
wherein R4 is an alkyl group, to the compound of formula 10a.
The compound according to formula 10a (shown above) can be used in another method of this invention to produce a compound of formula 11a: 
wherein Yxe2x88x92 is a suitable salt anion. In this method, the compound of formula 10a is converted, under sufficient conditions, to the compound of formula 11a.
The compounds and intermediates according to the invention advantageously can be used to produce nelfinavir mesylate: 
In one method, a compound of formula 10: 
wherein R3 is an aryl group or an alkyl group, is converted, under sufficient conditions, to a compound of formula 11: 
The compound according to formula 11 then is converted, under sufficient conditions, to a compound of formula 12: 
The compound according to formula 12 is then converted to nelfinavir mesylate.
A second method according to the invention for making nelfinavir mesylate (illustrated above) includes converting, under sufficient conditions, a compound of formula 10a: 
to a compound of formula 11a: 
wherein Yxe2x88x92 is a suitable salt anion. The compound of formula 11a then is converted, under sufficient conditions, to a compound of formula 12 (shown above), which then is converted, under sufficient conditions, to nelfinavir mesylate.
The present inventors have discovered useful novel intermediate compounds that can be used in several novel reaction schemes to make nelfinavir mesylate. More specifically, the present invention relates to new processes that have been developed to prepare nelfinavir free base, the penultimate intermediate of the raw drug nelfinavir mesylate (Schemes 1, 2 and 3). In addition to being operationally simple, these processes utilize cheap, commercially available raw materials and offer an alternative to the more expensive chloro-alcohol based chemistry that has been used for manufacture (see HIV Protease Inhibitors, Intl. Pat. No. WO 95/09843). These new processes proceed through cyclic sulfates of general structure 6 or 6a: 
where R3 is aryl or alkyl and X is a leaving group. These cyclic sulfates are novel 4-carbon electrophilic species derived from (2S,3S)-(xe2x88x92)tartaric acid, a substance commercially available from many suppliers. Such intermediates are new chemical entities that possess leaving group ability at 4 contiguous carbons. Such ambident electrophilicity can be selectively unmasked in the production of 4 carbon units useful in nelfinavir free base synthesis. These intermediates are general synthons for the production of 4-carbon units bearing 4 carbon-heteroatom bonds, two of which are at stereogenic centers.
Using the intermediates and compounds described in this application, as well as the methods described herein, one can prepare nelfinavir free base and nelfinavir mesylate, compounds useful as HIV-protease inhibitors. The following detailed description describes various specific examples and reaction schemes that can be used in accordance with this invention. These examples and reaction schemes should be considered as illustrating the invention and not as limiting the same.